The incidence and clinical characteristics of peripheral arthritis in polymyalgia rheumatica and temporal arteritis: a prospective study of 231 cases

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1 Rheumatology 2000;39: The incidence and clinical characteristics of peripheral arthritis in polymyalgia rheumatica and temporal arteritis: a prospective study of 231 cases Department of Rheumatology, Central Hospital of Aust Agder, 4800 Arendal, Norway Abstract Objective. To evaluate the incidence and characteristics of peripheral arthritis in polymyalgia rheumatica and temporal arteritis, and to ascertain the incidence of rheumatoid arthritis among such cases. Patients and methods. In total, 231 patients were selected from a prospective populationbased study. All patients were clinically examined on several occasions and followed until cessation of therapy and permanent disease remission. Results. Of the 231 cases, 38.5% presented peripheral arthritis either at diagnosis or during the disease course. At diagnosis, peripheral arthritis was not observed among patients with temporal arteritis. Peripheral arthritis occurring during the disease course was more often polyarticular and needed additional treatment more frequently than joint inflammation presenting at diagnosis. Only one case had distal pitting oedema. Rheumatoid arthritis developed in 4.8% of the cases and exclusively among patients with polymyalgia rheumatica. Conclusion. Aetiopathogenic differences may exist between polymyalgia rheumatica and temporal arteritis as peripheral arthritis and the development of rheumatoid arthritis were observed among the former patient group only. KEY WORDS: Polymyalgia rheumatica, Temporal arteritis, Peripheral arthritis. Polymyalgia rheumatica (PMR) and temporal arteritis own preliminary observations [3] which indicated that ( TA) have traditionally been regarded as one disease peripheral arthritis may occur exclusively in PMR and expressing different clinical manifestations. This view not in TA may also emphasize important aetiopathogenic has been based on findings of a common genetic disease differences between PMR and TA. susceptibility [1] and a rather frequent coexistence of It has also been suggested that the peripheral arthritis the two syndromes [ 2]. However, the significant clinical developing in PMR may be difficult to discriminate differences between PMR and TA may suggest separate from that occurring in elderly onset seronegative aetiopathogeneses. rheumatoid arthritis ( RA) [1, 4 6] and remitting First, the occurrence of arteritis in PMR may not be seronegative symmetrical synovitis with pitting oedema as frequent as previously anticipated [2]. According to ( RS3PE) [7]. Thus, PMR may occasionally be more our own observations [3], arteritis of the temporal artery related to RA and RS3PE which affect synovial tissues is detected histologically in only 6% of PMR when than to TA whose predominant pathological finding is biopsies are performed in patients lacking clinical mani- arteritis. However, the frequency of RA development festations of concurrent TA. Second, the overwhelming during the disease course of PMR is not finally majority of patients of the PMR/TA disease complex determined. suffer from pure PMR without clinical signs and symptoms It was thus of interest to study the incidence and of TA [3]. Third, the frequent occurrence of characteristics of peripheral arthritis in a large group of peripheral arthritis in PMR may suggest that components unselected patients with PMR and TA, followed pro- in synovial tissues represent important antigenic spectively from the onset of disease and throughout the targets in the aetiopathogenesis of PMR. Finally, our entire disease course. The longitudinal design of the survey also allowed us to estimate the incidence of RA Submitted 23 July 1999; revised version accepted 20 September among such patients and to explore possible aetio- Correspondence to: J. T. Gran, Revmatologisk Avdeling, Aust pathogenic differences between PMR and TA. Agder Sentralsjukehus, 4800 Arendal, Norway British Society for Rheumatology

2 284 Materials and methods Geography The county of Aust Agder, south Norway is mainly located on the coast, and in the period the total population averaged inhabitants of whom 29% were 50 yr or older. Methods Prior to the start of the study, all physicians in the county of Aust Agder were informed of the study, and asked to refer all patients suspected of having PMR or TA to the Department of Rheumatology as soon as possible and before initiating drug therapy. The county of Aust Agder has one general hospital including departments of rheumatology, internal medicine, geriatrics and ophthalmology. There are no private practising rheumatologists in the region. In order to assure some minimum length of observation, only patients with a disease onset during the period were included in the study. They were fol- RA lowed up at 3-month intervals the first year, thereafter rheumatoid factors ( Waaler s test), and antinuclear antibodies. Radiological examinations were performed only if development of erosive arthritic disease was suspected or the patient was evaluated for surgical intervention. Statistics The chi-squared test, Fisher s exact test and Student s t-test were used for statistical analyses, and a P value of 0.05 or less was accepted as significant. Results Classification of patients Prior to the study, 26 cases were excluded. Ten patients were withdrawn from the investigation due to coexisting RA and 16 patients were lost during the follow-up. In total, 231 patients, 151 females and 80 males were studied. There were 187 cases of pure PMR, 29 cases of TA and 15 patients with both PMR and TA. The development of RA was observed in 11 patients twice yearly until cessation of therapy and permanent (4.8%), six females and five men, during the observation disease remission. All patients were examined by a period ( Table 1). Of the 11 cases, 10 cases had pure rheumatologist. In addition, all hospital records with a PMR and one case suffered from both PMR and TA. diagnosis of either PMR or TA were carefully reviewed None of the patients with pure TA developed RA. The to estimate the number of patients with such disorders mean duration of PMR at onset of RA was 62.3 months who had been treated by the departments of internal (median 59 months, range months). Nine of the medicine, geriatrics and ophthalmology. 11 patients developed RA more than 3 yr after the onset The American College of Rheumatology (ACR) cri- of PMR. Radiological examinations of hands and feet teria [ 8] for TA were applied but only cases with were performed in eight cases, of whom five had erosive histologically proven giant cell arteritis were included. changes typical of RA. Serum rheumatoid factors were For PMR, patients meeting either the criteria suggested determined in all cases and six of these cases possessed by Bird et al. [ 9] or those of Hamrin [10] were selected such autoantibodies. Thus, seropositive erosive RA for the study. Thus, all patients with PMR included in developed in three cases (1.3%). the present study had bilateral pain and/or stiffness of the shoulder and/or pelvic girdle which could not be Frequency of peripheral arthritis explained by diseases other than PMR. The cases were Table 2 shows the frequencies of peripheral arthritis in divided into the following groups: (A) Patients exhibit- the various groups. In total, 38.5% of the patients ing peripheral arthritis at diagnosis only. (B) Patients presented peripheral arthritis. Peripheral arthritis occurwith peripheral arthritis at diagnosis and later during ring exclusively at diagnosis was seen in 14.7% of the the disease course. (C) Patients without peripheral arthritis at diagnosis, but developing such features during TABLE 1. Characteristics of patients developing RA during disease the disease course. (D) Patients in whom peripheral course of PMR (n = 11) arthritis was never observed. The mean observation time was 56.8, 75.4, 75.6 and 58.0 months in groups A, B, C Duration of and D, respectively. Peripheral arthritis was defined Age at PMR at Erosive onset onset of X-ray clinically as swelling and pain or local warmth in a joint. No. Sex of PMR Diagnosis RA (months) changes RF Magnetic resonance imaging and scintigraphic examinations were not performed. 15 F 70 PMR+TA F 60 PMR Laboratory examinations 99 F 65 PMR F 57 PMR 105 NE + The following blood tests were performed in all patients: 244 F 61 PMR 93 + complete blood count including white cell count and 383 F 63 PMR 62 + thrombocytes, haemoglobin, erythrocyte sedimentation 9 M 63 PMR 44 NE rate ( Westergren) ( ESR), C-reactive protein (CRP), 246 M 77 PMR creatinine, creatine kinase, alaninoaminotransferase, 277 M 61 PMR M 71 PMR 44 NE + aspartateaminotransferase, gammaglutamyltranspepti- 304 M 76 PMR dase, alkaline phosphatase, thyroxin ( T4), thyroid stimulating hormone, serum electrophoresis, uric acid, NE, not examined; RF, rheumatoid factor.

3 Peripheral arthritis in PMR and TA 285 TABLE 2. Frequencies (%) of peripheral arthritis in PMR and TA Patient group PMR TA PMR and TA Total (n = 187) (n = 29) (n = 15) (n = 231) Number % Number % Number % Number % Arthritis at diagnosis only (A) Arthritis at diagnosis and later (B) Arthritis at follow-up only (C) Arthritis not demonstrated (D) cases, 7.8% presented peripheral arthritis both at diagno- The most commonly involved joints were the knees sis and during follow-up, and 16% had no peripheral (46.7%), metacarpophalangeal joints (MCP) (42.0%) arthritis at diagnosis but developed such manifestations and wrists (42.1%). Sternoclavicular joint inflammation later on. At diagnosis, peripheral arthritis was not seen was seen in three patients (2.8%) of whom one had in TA, while one TA patient developed transient erosive changes at X-ray. Distal pitting oedema was monoarticular peripheral arthritis during the observation recorded in one case only. Isolated Baker cysts without period. concomitant detectable knee arthritis were seen in five Characteristics of the arthritis cases. At diagnosis, the frequencies of monoarthritis, oligoarthritis Therapy of arthritis and polyarthritis were 34.0, 62.3 and 3.8%, All 231 patients except one were treated with oral respectively. During the disease course, the correspond- corticosteroids (prednisolone). Therapy of arthritis preing frequencies were 26.9, 48.1 and 25%, respectively. senting at diagnosis was recorded in 51 cases. Of these, Polyarticular joint inflammation was significantly more 44 (86.3%) required no therapy in addition to oral frequent during the disease course than at diagnosis corticosteroids, while non-steroidal anti-inflammatory (P = 0.005), even when calculations were performed drugs (NSAIDs) were prescribed in three cases and after exclusion of patients developing RA. intra-articular corticosteroid injections were given to Among cases with peripheral arthritis contracted four patients. During the observation period, therapy exclusively during the disease course, 25 of 37 (67.6%) of arthritis was recorded in 55 cases. Of these, 19 cases had one episode of arthritis, while 12 patients ( 32.4%) (34.5%) were given no additional treatment, 17 cases had multiple episodes of arthritis. Among those with (30.9%) were given NSAIDs, 15 cases (27.3%) received only one episode, the first episode developed during the intra-articular corticosteroid injections, seven patients first year of disease in 68% (range 1 86 months). Among (12.7%) were given disease-modifying anti-rheumatic those with multiple episodes, six of 12 ( 50%) developed drugs (DMARDs) and two patients (3.6%) had surgical their first arthritic attack during the first year of disease knee synovectomies. The frequency of additional treat- (range 6 53 months), while the last episode was seen as ment was significantly higher during follow-up than at late as after 147 months of disease (range months). diagnosis (P = 0.001). Distribution of arthritis Comparison between patients with and without arthritis Table 3 shows joint involvement at diagnosis and during The mean age at onset of disease was similar in patients the observation period. The distribution of joint involve- with and without peripheral arthritis (69.5 and 72.2 yr, ment was similar at diagnosis and during observation. respectively). Arthritis occurred in 41.5% of females with PMR compared with 53.6% among male PMR TABLE 3. Joint involvement (%) in PMR and TA (P = 0.14). The mean ESR at diagnosis was 66.9 among cases At diagnosis During disease Joint involvement (n = 53) course (n = 54) without peripheral arthritis, 67.9 in those with arthritis at diagnosis only, and 85.6 among those who developed Wrist peripheral arthritis during the disease course but exhib- MCP ited no arthritis at diagnosis. Similarly, the mean CRP Knee at diagnosis was higher ( 88.6) among those with arthritis PIP Ankle later on exclusively when compared with patients with Hip arthritis at diagnosis ( 65.0) and compared with cases Elbow without arthritis ( 59.7). However, the differences in MTP ESR and CRP between the various groups did not reach Sternoclavicular statistical significance. MTP, metatarsophalangeal joints; PIP, proximal interphalangeal The mean minimum dose of oral corticosteroid joints. (prednisolone) during the first year of disease was 5.5 mg

4 286 in cases with arthritis at diagnosis, 6.4 mg in those with disorders. An alternative explanation would, however, arthritis during the disease course only and 5.7 mg be that a common genetic predisposition exists in PMR among patients exhibiting no joint inflammation. These and TA regarding disease susceptibility, but that other differences did not reach statistical significance. The yet unknown factors influence the clinical expressions mean dose of prednisolone at the start of treatment in of the syndrome. The present observations support the patients with PMR having arthritis at diagnosis only view of two separate disorders, or one common was 18.4 mg, 31.5 mg in patients with arthritis both at disease in which host susceptibility influences clinical diagnosis and later, 27.7 mg in those with arthritis later expressions. only and 22.7 mg in cases without arthritis. On the other hand, RA developed rather infrequently among the patients which lends little support to suggestions of PMR and RA being closely related. In fact, Discussion seropositive erosive RA developed in only 1.2% of our The prospective design of the present study allowed us cases. Moreover, the peripheral arthritis in PMR that to study peripheral arthritis both prior to initiation of presented both early and late during the disease course corticosteroid therapy and during the disease course. As was most often of the oligoarticular type rather than only 16 patients (6.5%) were lost on follow-up, the polyarthritis which prevails in RA. In a recent study present patient material appears highly representative [12] of 128 patients with giant cell arteritis, six patients of the total sample. Moreover, this epidemiological (4.7%) developed polyarthritis compatible with a diagnosis survey was performed in a county having only one single of RA. However, none possessed serum rheumasurvey hospital and no private practising rheumatologists, toid factors and only one patient developed radiological which further emphasizes the representativeness of the joint erosions. These findings of a rare occurrence of patients. As the patients were followed for the entire RA among patients with the PMR/TA disease complex disease course, the risk of including cases with diseases are in agreement with earlier studies [20, 21], and other than PMR and TA but manifesting polymyalgic clearly show that RA and PMR represent two separate symptoms was substantially reduced. However, only disorders. clinically detectable peripheral arthritis was recorded, We were unable to confirm recent findings of a and routinely performed ultrasonographic examinations frequent coexistence of RS3PE and PMR [12]. Only [11] and magnetic resonance imaging [1] could have one case with pitting oedema was observed, but it should revealed an even higher incidence of such manifestations. be noted that the present prospective study was not It should be noted that in the present study, cases constructed to look specifically for this clinical feature. with pre-existing RA were excluded from the calculations. Some cases may therefore have been overlooked. The cases had long-standing seropositive erosive However, the patients were carefully evaluated at regular RA and whether the peripheral arthritis was due to intervals and a frequent occurrence of a RS3PE-like PMR or represented an exacerbation of their RA was clinical picture would most likely have been noted. Thus, rather difficult to evaluate. The typical characteristics of the results of the present investigation do not indicate RA made it unlikely that their pre-existing peripheral significant relations between PMR and RS3PE. arthritis was a preceding manifestation of PMR. Similar to earlier findings [1], the most frequently The total incidence of peripheral arthritis was rather involved joints were the wrists, MCPs and knees. It has high ( 38.5%), confirming previous observations [4, 5, been suggested that the involvement of extra-articular 12 14], but at variance with others [15]. An important synovial tissues is of aetiopathogenic importance in finding was that peripheral arthritis occurred almost PMR [1], but the frequent involvement of such distal exclusively in patients with PMR, and no case of peri- joints as the wrists and MCPs hardly explains the pheral arthritis at onset of TA was observed. A possible predominant proximal myalgia occurring in PMR. explanation of why this particular absence of peripheral Arthritis may, however, have been present in shoulders arthritis in TA has been infrequently noted by previous and hips without producing sufficient clinical findings workers [16], may be that most often PMR and TA to awaken our suspicion, a finding that has been reported have not been evaluated as separate disease groups. The by others [5, 11]. Thus, the present results do not speak observation may, however, to some extent indicate against the hypothesis of synovial involvement being of important aetiopathogenic differences between PMR primary importance in the development of PMR. and TA. Such a view is further emphasized by our However, as the overwhelming majority of our patients previous findings of histological arteritis being a rather with peripheral arthritis recovered completely, the syn- rare finding in patients with pure PMR [3, 17]. Thus, ovial pathogenesis in PMR is clearly different from that synovial tissues appear as possible antigenic targets in of RA. Recent studies [1] employing hand and foot PMR while structures in the arterial wall are of aetio- magnetic resonance imaging have also shown that pathogenic significance in TA. inflammation of the tenosynovial sheaths may represent Studies of HLA molecules [18, 19] have not provided the hallmark of PMR. findings to determine the precise relationship between At diagnosis, few of the patients with peripheral PMR and TA. One concept is the presence of two arthritis required additional therapy for their arthritic different clinical expressions of the same disease, while manifestations. However, during the disease course, 41 another possibility is that PMR and TA are two separate of 60 events of peripheral arthritis required therapy in

5 Peripheral arthritis in PMR and TA 287 addition to oral corticosteroids. Moreover, polyarticular infiltration in synovial tissue from the shoulder of patients joint inflammation occurred significantly more fre- with polymyalgia rheumatica. Arthritis Rheum 1996;39: quently during the disease course than at diagnosis Neither the initial dose of corticosteroids nor the mainrheumatoid arthritis may be the same entity. J Rheumatol 6. Healey LA. Polymyalgia rheumatica and seronegative tenance dose during the first year of disease varied 1992;19: between these groups, and the mode of therapy could 7. Cantini F, Salvarani C, Olivieri I. Remitting seronegative thus not explain the discrepancies in the occurrence of symmetrical synovitis with pitting edema syndrome: a polyarthritis. However, the higher frequency of poly- prospective follow-up study and magnetic resonance arthritis again emphasized the fact that the late peri- imaging study. Ann Rheum Dis 1999;58: pheral arthritis was more severe than that presenting 8. Hunder GG, Bloch DA, Michel BA et al. The American early in the disease course. Most cases were, however, College of Rheumatology 1990 criteria for the classifica- managed on NSAIDs and local corticosteroid injections, tion of giant cell arteritis. Arthritis Rheum 1990;33: but DMARDs were employed in seven cases and two 9. Bird HA, Esselinckx W, Dixon ASTJ, Mowat AG, Wood knee synovectomies were performed. These findings call PHN. An evaluation of criteria for polymyalgia rheum- atica. Ann Rheum Dis 1979;38: for careful follow-up of patients with PMR, and suggest 10. Hamrin B. Polymyalgia arteritica. Acta Med Scand that such manifestations may be best treated by 1972;533(Suppl.):1 13. rheumatologists. 11. Koski JM. Ultrasonographic evidence of synovitis in axial In conclusion, the finding of a rather high incidence joints in patients with polymyalgia rheumatica. Br of peripheral arthritis both early and late in the disease J Rheumatol 1992;31: course of PMR may lend support to suggestions of 12. Salvarani C, Hunder G. Musculoskeletal manifestations synovial tissues being of aetiopathogenic significance in in a population cohort of patients with giant cell arteritis. this disease. The almost complete absence of peripheral Arthritis Rheum 1999;42: arthritis in TA suggests important aetiopathogenic 13. Henderson DRF, Tribe CR, Dixon ASJ. Synovitis in differences between PMR and TA, but the rather infrepolymyalgia rheumatica. Rheumatol Rehabil 1975; 14: quent development of RA among such cases does not 14. Healey LA. Long-term follow-up of polymyalgia rheumsupport the view of a close relationship between PMR atica: evidence for synovitis. Semin Arthritis Rheum and RA. Although most cases exhibiting peripheral 1984;13: arthritis are handled by the corticosteroid therapy 15. Kyle V, Tudor J, Wraight EP, Gresham GA, Hazleman already in use, the frequent need for NSAIDs, intra- BL. Rarity of synovitis in polymyalgia rheumatica. Ann articular corticosteroid injections and occasional Rheum Dis 1990;49: DMARD prescriptions during the disease course do 16. Noltorp S, Svensson B. High incidence of polymyalgia suggest that patients with PMR are best treated and rheumatica and giant cell arteritis in a Swedish community. observed by rheumatologists. Clin Exp Rheumatol 1991;9: Gran JT, Myklebust G. The incidence of polymyalgia rheumatica and temporal arteritis in the county of Aust References Agder, South Norway: A prospective study J Rheumatol 1997;24: Salvarani C, Cantini F, Olivieri I, Hunder GS. Polymyalgia 18. Dababneh A, Gonzales-Gay MA, Garcia-Porrua C, rheumatica: a disorder of extraarticular synovial struc- Hajeer W, Ollier W. Giant cell arteritis and PMR can be tures? J Rheumatol 1999;26: differentiated by distinct patterns of HLA class II associ- 2. Fauchald P, Rygvold O, Øystese B. Temporal arteritis and ation. J Rheumatol 1998;25: polymyalgia rheumatica. Ann Intern Med 1972;77: Guerne PA, Salvi M, Seitz M et al. Molecular analysis of 3. Myklebust G, Gran JT. A prospective study of 287 patients HLA-DR polymorphism in polymyalgia rheumatica. with polymyalgia rheumatica and temporal arteritis: clin- J Rheumatol 1997;24: ical and laboratory manifestations at onset of disease and 20. Ginsburg WW, Cohen MD, Hall SB, Vollertsen RS, at the time of diagnosis. Br J Rheumatol 1996;35: Hunder GG. Seronegative polyarthritis in giant cell arter- 4. O Duffy JD, Hunder GG, Wahner HW. A follow-up study itis. Arthritis Rheum 1985;28: of polymyalgia rheumatica: evidence of chronic axial 21. Salvarani C, Rossi F, Macchioni P et al. Synovitis in synovitis. J Rheumatol 1980;7: polymyalgia rheumatica: an immunogenetic study. Br 5. Meliconi R, Pulsatelli L, Uguccioni M et al. Leukocyte J Rheumatol 1992;31:720.